Stilbene derivatives have been shown to have a wide range activities and are widely distributed in nature as natural constituentes of plants. There is a growing interest in stilbene derivatives because of a range of activities that have been observed in some of the naturally occurring as well as some of the synthetic stilbenes. Activities include antibiotic (Hu, K., et al., Canadian Journal of Microbiology, 1998, 44, 1072), antileukemic (Mannila, et al., Phytochemistry, 1993, 33, 813), carcinnostatic (EP 641, 767), and protein-tyrosine kinase inhibitory activity (Thakkar, K.; et al., J. Med. Chem., 1993, 36,2950). With the isolation of 5-(2-phenylethenyl)-2-i-propyl-1,3-benzenediol from the bacterial species Photorhabdus, a series of its analogues have been designed and synthesized as useful agents or ingredients to treat inflammation and psoriasis and to interfere with protein kinase (Webster et al. WO 01/42231).
It is well established that T lymphocytes (T-cells) play an important role in regulating the immune response. T-cells are closely associated with a wide variety of cytokines such as interleukines (IL), tumor necrosis factors (TNF), interferons (IFN) and granulocyte macrophage colony. T-cell activation and proliferation, and the cytokines associated with them, mediate a wide range of physiological activities in the immune system and in pathogenic inflammation. For example, inhibitors of certain ILs are potentially beneficial for Th2 predominant diseases, while inhibitors of IFN-γ and TNF-α are useful for treatment of Th1 induced immune diseases.
Macrophages are very important components of the host defense system, but they are also involved in the development of tissue injury during inflammation in some human disease. Efficient antagonists can block subsequent symptoms (skin redness, edema, pain and dysfunction) of inflammation. CD86 expression, nitric oxide and TNF-α production are experimental indicators of macrophage function in vivo. CD86 expression by antigen presenting cells including dendritic cells, macrophages and activated B cells is necessary for interaction with T-cell CD28, which is necessary for the T-cells to be fully activated. Nitric oxide is a potent microbiological macrophage product. TNF-α is a pro-inflammatory cytokine important in recruitment and stimulation of inflammatory cells.
Neutrophils predominate over other cell types in many variants of acute and chronic inflammatory conditions. IL-8 is a chemokine produced by neutrophils that in addition to being chemotactic for monocytes and other leukocytes, also activates neutrophils. Down-regulation of neutrophil IL-8 generation may represent a negative feedback mechanism helping to control neutrophil inflammatory activity by preventing further neutrophil recruitment and activation.
Some cytokines mediate a broad inflammatory and immune response as a result of infection or injury and/or other factors. Other cytokines have more specific functions. The complex interplay of these many different cytokine functions with immune cells is essential for the appropriate and optimal immune function. Activation of T-cells is often the initiating event in many of the immune, inflammatory and autoimmune diseases. Accordingly, compounds that can effectively interfere with cytokine formation have utility in preventing and treating related disorders.
IL-2, a 15-kDa protein, is secreted by T-cells upon antigen stimulation and is required for normal immune responsiveness. IL-2 stimulates the proliferation and activation of B and T-cells and is a potent cytokine that can lead to cellular activation and proliferation. IL-2 receptors are found on activated B-Cells, lipolysaccharide treated monocytes, and many T-cells. Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo [T. A. Waldmann, Immunol. Today, 14, 270 (1993)].
One of the other cytokines is interleukin-8 (IL-8), which has been shown to be a powerful substance for initiating and sustaining inflammatory reactions. IL-8 is also known under the names neutrophil activating peptide or monocyte derived neutrophil activating peptide. It attracts neutrophils by chemotaxis and triggers the release of myeloperoxidase. IL-8 is believed to be associated with diseases such as psoriasis, allergic reactions, rheumatic afflictions and inflammations of the skin and the lungs.
IFN-γ is a member of the interferon family and was produced originally upon mitogenic induction of lymphocytes. IFN-γ is secreted from CD4+ Th1 cells, CD8 cells, gamma/delta T-cells and activated natural killer cells. It plays a role in activating lymphocytes to enhance anti-microbial and anti-tumor effects. In addition, it plays a role in regulating the proliferation, differentiation, and response of lymphocyte subsets. IFN-γ is synthesized by lymphocytes in response to mitogens and induces major histocompatibility complex (MHC) Class II antigen expression. IFN-γ promotes a number of pro-inflammatory aspects of immune responses including the up-regulation of MHC. For a number of autoimmune diseases, the disease-associated inflammatory process is associated with an increased availability of IFN-γ. IFN-γ may have a strong impact on autoimmune disease progression or resolution, actions that may be specific for a particular condition.
Agents that modulate the activities of these cells and the associated cytokine activities are very useful to science and medicine. We now have found many novel stilbene compounds, and have shown that these novel compounds have effect on T lymphocytes, macrophages, neutrophils and mast cells and mediates a variety of immune and inflammatory activities. Accordingly, the invention provides novel compounds, their use, pharmaceutical composition and process for producing these compounds.